The objective of this proposal is to clone the gene that is primarily responsible for the genetic predisposition to primary antiphospholipid antibody syndrome (PAPs). We have identified 12 multiplex families with PAPs including two families that each have six affected individuals that meet stringent diagnostic criteria. Ten additional families have been identified but incompletely characterized. Additional large multiplex families will be sought using a nation wide screening through contacts with hematologists and rheumatologists at academic center. Current modeling suggests that PAPs is inherited in an autosomal dominant trait with variable penetrance. Thus, the familial form of this disease may be attributable to molecular defects at a single major genetic locus. Data simulations suggest that the currently obtained families will allow the chromosomal assignment of the predominant susceptibility gene if polymorphic markers are examined at a 45 cM interval throughout the genome. With the availability of over 2000 characterized microsatellites such a genome sweep can be readily performed. All family members will come to the GCRC for evaluation for the presence of an antiphospholipid antibody. Affected family members will also be evaluated for the integrity of the natural anticoagulant mechanisms and the fibrinolytic pathway. Antiphospholipid antibodies will be characterized for their ability to bind to beta2-glycoprotein 1, prothrombin, protein C, and protein S, in the presence of various phospholipid surfaces. These studies will define the coagulation defect(s) in these kindreds, may be critical in determining whether different kindreds are likely to have the same genetic defect, and will provide additional phenotypic criteria. In addition, these studies may identify candidate genes. Sixteen family members have been evaluated. We will continue to evaluate patients and family members over the next year.